Quinazoline derivatives of general formula (I) are known from WO 02/50043 and WO 04/074263, which describe compounds with valuable pharmacological properties, including in particular an inhibitory effect on signal transduction mediated by tyrosine kinases and an inhibitory effect on signal transduction mediated by Epidermal Growth Factor-Receptor (EGF-R). Therefore, compounds of this type are suitable for the treatment of diseases, particularly for the treatment of tumoral diseases, diseases of the lungs and airways and diseases of the gastro-intestinal tract and the bile ducts and gall bladder.
WO 2002/50043 discloses a method of production in which aminocrotonyiamino-substituted quinazolines (I) are prepared in a one-pot reaction from the corresponding aniline component (II), bromocrotonic acid, oxalyl chloride and a secondary amine (see Diagram 1).

The process is not well suited to technical use on an industrial scale, as the yields obtained are at most 50% and as a rule laborious purification by column chromatography is needed. Moreover the educt bromocrotonic acid is not commercially available in large amounts and the corresponding methyl bromocrotonate is only available with a purity of about 80%.
WO 2005/037824 describes an alternative process for preparing aminocrotonylamino-substituted quinazoline derivatives of general formula (I) by Wittig-Horner-Emmons reaction of dialkyl-phosphonoacetamido-substituted quinazolines (III) with a 2-aminoacetaldehyde (IV) (Diagram 2), while instead of the aldehyde (IV) it is possible to use the corresponding hydrate or an acetal (e.g. the diethylacetal corresponding to (IV)), from which the aldehyde is liberated (beforehand or in situ).

The educts of formula III may be obtained according to WO 2005/037824 as follows:

Both in the prior art described above and within the scope of the invention described hereinafter, the groups Ra, Rb, Rc, Rd, R1 and R2 have the following meanings:    Ra denotes a benzyl, 1-phenylethy) or 3-chloro-4-fluorophenyl group,    Rb denotes a methyl, ethyl, isopropyl, cyclopropyl, 2-methoxyethyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl, tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or tetrahydropyran-4-yl-methyl group,    Rc denotes a methyl, ethyl or 2-methoxyethyl group or    Rb and Rc together with the nitrogen atom to which these groups are bound denote a morpholino or homomorpholino group optionally substituted by one or two C1-3-alkyl groups,    Rd denotes a cyclopropylmethyl, cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl, tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or tetrahydropyran-4-yl-methyl group, and    R1 and R2 each independently of one another denote a C1-4-alkyl group, for example each denote an ethyl group.
By a homomorpholino group is meant the next highest ring-homologue of the morpholino group, namely the group of formula

Starting from commercially obtainable 4-chloro-anthranilic acid (V), reacting with formamidine acetate (step a) produces the quinazolinone (VI), which is then nitrated using sulphuric acid and concentrated nitric acid (step b). The desired regioisomer (VII) is then chlorinated using thionyl chloride in acetonitrile (step c) and the chlorination product (IX) is reacted in situ with the corresponding amine Ra—NH2 (step d). The compound of formula (X) thus obtained is reacted by base-catalysed nucleophilic substitution with Rd—OH to form the compound (XI) (step e), which is in turn converted by hydrogenation into the corresponding aminoquinazoline (XII) (step f). The aminoquinazoline (XII) is then converted by reaction with a di-(C1-4-alkyl)-phosphonoacetic acid, e.g. with diethylphosphonoacetic acid, in suitable solvents such as tetrahydrofuran (THF), dimethylformamide (DMF) or ethyl acetate, after corresponding activation, for example with 1,1-carbonyldiimidazole, 1,1-carbonylditriazole or propanephosphonic anhydride, into the dialkyl-phosphonoacetamido-substituted quinazoline (III) needed for the Wittig-Horner-Emmons reaction.
The process described in WO 2005/037824 also has a number of serious disadvantages for technical use. For example, the use of thionyl chloride in Step (c) is problematic for safety reasons. The cyclic or heterocyclic alcohols needed to introduce the group Rd in an excess of about 2 equivalents (eq) are starting materials which are difficult to obtain or expensive, and phase transfer catalysis, for example using 18-crown-6, is also needed to react them according to step (e) in Diagram 3 on an industrial scale. The reaction product has to be purified by recrystallisation to eliminate the phase transfer catalyst. The hydrogenation of step (f) is carried out with the addition of acetic acid, if the educt contains a chlorine atom, so as to prevent the formation of dechlorlinated by-products which are difficult to strip out. The addition of acetic acid causes traces of the nickel needed as catalyst to be dissolved, and this is then entrained into the final step and gives rise to a heavy metal problem which is unacceptable for pharmaceutical use. Moreover, the throughput of individual partial reactions is in need of improvement; for example the throughput in step (e) according to Diagram 3 is only 1/60 (1 kg of starting material require a reactor volume of 60 l).
In the light of the disadvantages of the known production method as described above, the problem of the present invention is to provide an improved method, suitable for synthesis on an industrial scale, which permits the safe preparation of aminocrotonylamino-substituted quinazoline derivatives (I) using easily obtainable starting materials of high purity and at a lower technical cost.